Comment on evolutionary dynamics of cancer multidrug resistance in response to olaparib and photodynamic therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Madariaga A
PROVIDER: S-EPMC8529546 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI:http://dx.doi.org/10.7554/eLife.00747.001.
| S-EPMC3691570 | biostudies-literature
Project description:Curcumin (CUR) possesses photosensitive anti-tumor activity. However, photoactive CUR mainly targets tumor cells sensitive to chemotherapy, whereas the effect on multi-drug resistant cancer cells has not been fully investigated. The study aimed to investigate the anti-tumor activity of CUR on resistant MCF-7/ADM cells and its underlying mechanism providing insights into CUR-mediated PDT and a reference for reversing multidrug resistance. Cell apoptosis and morphological changes were detected by Annexin V-FITC/PI double staining and immunofluorescence, respectively. The apoptosis mechanism of CUR-mediated PDT was investigated by detecting the levels of reactive oxygen species (ROS), mitochondrial membrane potential, and related proteins. MTT and apoptosis results showed that CUR-mediated PDT significantly enhanced cytotoxicity and induced considerable cell apoptosis. After treatment with CUR-mediated PDT, cells became round in shape and shrunk, F-actin was loosely arranged, and the nucleus decreased in size. In addition, the level of ROS increased over time compared to the control and peaked at 6 h. CUR-mediated PDT induced alterations in the mitochondrial membrane potential, increased the release of mitochondrial cytochrome C (Cyt-c), and downregulated caspase-3/7/9, PARP, and P-gp. In conclusion, CUR-PDT induced apoptosis in resistant MCF-7/ADM cells primarily through endogenous mitochondrial apoptosis pathway. Besides apoptosis activation in resistant cells, the reverse of multidrug resistance was ascribed to the downregulation of P-gp expression to a degree.
| S-EPMC9047416 | biostudies-literature
Project description:The selection of chemotherapy drugs is based on the cytotoxicity to specific tumor cell types and the relatively low toxicity to normal cells and tissues. However, the toxicity to normal cells poses a major clinical challenge, particularly when malignant cells have acquired resistance to chemotherapy. This drug resistance of cancer cells results from multiple factors including individual variation, genetic heterogeneity within a tumor, and cellular evolution. Much progress in the understanding of tumor cell resistance has been made in the past 35 years, owing to milestone discoveries such as the identification and characterization of ABC transporters. Nonetheless, the complexity of the genetic and epigenetic rewiring of cancer cells makes drug resistance an equally complex phenomenon that is difficult to overcome. In this review, we discuss how the remarkable changes in the levels of glucose, IGF-I, IGFBP-1 and in other proteins caused by fasting have the potential to improve the efficacy of chemotherapy against tumors by protecting normal cells and tissues and possibly by diminishing multidrug resistance in malignant cells.
| S-EPMC3573885 | biostudies-literature
Project description:Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation.
| S-EPMC4520758 | biostudies-literature
Project description:Photodynamic therapy (PDT) has emerged as a potential therapeutic option for most localized cancers. Its high measure of specificity and minimal risk of side effects compared to other therapies has put PDT on the forefront of cancer research in the current era. The primary cause of treatment failure and high mortality rates is the occurrence of cancer resistance to therapy. Hence, PDT is designed to be selective and tumor-specific. However, because of complex biological characteristics and cell signaling, cancer cells have shown a propensity to acquire cellular resistance to PDT by modulating the photosensitization process or its products. Fortunately, nanotechnology has provided many answers in biomedical and clinical applications, and modern PDT now employs the use of nanomaterials to enhance its efficacy and mitigate the effects of acquired resistance. This review, therefore, sought to scrutinize the mechanisms of cellular resistance that affect the therapeutic response with an emphasis on the use of nanomaterials as a way of overriding cancer cell resistance. The resistance mechanisms that have been reported are complex and photosensitizer (PS)-specific. We conclude that altering the structure of PSs using nanotechnology is an ideal paradigm for enhancing PDT efficacy in the presence of cellular resistance.
| S-EPMC7407821 | biostudies-literature
Project description:Photodynamic therapy (PDT) is a treatment which uses light-activated compounds to produce reactive oxygen species, leading to membrane damage and cell death. Multicellular cancer spheroids are a preferable alternative for PDT evaluation in comparison to monolayer cell cultures due to their ability to better mimic in vivo avascular tumour characteristics such as hypoxia and cell-cell interactions, low cost, and ease of production. However, inconsistent growth kinetics and drug responsiveness causes poor experimental reproducibility and limits their usefulness. Herein, we used image analysis to establish a link between human melanoma C8161 spheroid morphology and drug responsiveness. Spheroids were pre-selected based on sphericity, area, and diameter, reducing variation in experimental groups before treatment. Spheroid morphology after PDT was analyzed using AnaSP and ReViSP, MATLAB-based open-source software, obtaining nine different parameters. Spheroids displayed a linear response between biological assays and morphology, with area (R2 = 0.7219) and volume (R2 = 0.6138) showing the best fit. Sphericity, convexity, and solidity were confirmed as poor standalone indicators of spheroid viability. Our results indicate spheroid morphometric parameters can be used to accurately screen inefficient treatment combinations of novel compounds.
| S-EPMC8637197 | biostudies-literature
Project description:Chemotherapeutic multidrug resistance (MDR) is the major hindrance for clinical therapy of colorectal cancer (CRC). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with selective cytotoxicity might overcome MDR of CRC cells. Unfortunately, cross-resistance to TRAIL has been detected in many CRC cells, suggesting the need to combine TRAIL with sensitizers to combat refractory CRC. Our purpose is to explore the potential of combination therapy of TRAIL and tumor-cell targeted photodynamic therapy (PDT) in combating CRC with both chemotherapeutic MDR and TRAIL resistance. Methods: Tumor cell-targeted PDT was performed using a Ze-IR700 photosensitizer with high affinity for epidermal growth factor receptor (EGFR). The impact of PDT on the gene expression of CRC cells was revealed by RNA sequencing. The synergistic antitumor effect of long-acting TRAIL and PDT was evaluated in mice bearing tumor grafts of CRC cells with both chemotherapeutic MDR and TRAIL resistance. Results: Chemotherapeutic MDR and TRAIL resistance are common in CRC cells. Pretreatment of CRC cells with tumor cell-targeted PDT significantly (10-60 times) increased the sensitivity of these CRC cells to TRAIL by upregulating death receptors. Combination therapy, but not monotherapy, of long-acting TRAIL and PDT greatly induced apoptosis of CRC cells, thus efficiently eradicated large (~150 mm3) CRC tumor xenografts in mice. Conclusions: Tumor cell-targeted PDT extensively sensitizes CRC cells to TRAIL. Combination therapy of long-acting TRAIL and PDT is promising to combat CRC with both chemotherapeutic MDR and TRAIL resistance, which might be developed as a novel strategy for precision therapy of refractory CRC.
| S-EPMC7977453 | biostudies-literature
Project description:Conventional systemic therapy for disseminated breast cancer is based on the general assumption that the greatest patient benefit is achieved by killing the maximum number of tumor cells. While this strategy often achieves a significant reduction in tumor burden, most patients with metastatic breast cancer ultimately die from their disease as therapy fails because tumor cells evolve resistance. We propose that the conventional maximum dose/maximum cell kill cancer therapy, when viewed from an evolutionary vantage, is suboptimal and likely even harmful as it accelerates evolution and growth of the resistant phenotypes that ultimately cause patient death. As an alternative, we are investigating evolutionary therapeutic strategies that shift the treatment goal from killing the maximum number of cancer cells to maximizing patient survival. Here we introduce two novel approaches for systemic therapy for metastatic breast cancer, considering the evolutionary nature of tumor progression; adaptive therapy and double-bind therapy.
| S-EPMC4258899 | biostudies-literature
Project description:Resistance against different antibiotics appears on the same bacterial strains more often than expected by chance, leading to high frequencies of multidrug resistance. There are multiple explanations for this observation, but these tend to be specific to subsets of antibiotics and/or bacterial species, whereas the trend is pervasive. Here, we consider the question in terms of strain ecology: explaining why resistance to different antibiotics is often seen on the same strain requires an understanding of the competition between strains with different resistance profiles. This work builds on models originally proposed to explain another aspect of strain competition: the stable coexistence of antibiotic sensitivity and resistance observed in a number of bacterial species. We first identify a partial structural similarity in these models: either strain or host population structure stratifies the pathogen population into evolutionarily independent sub-populations and introduces variation in the fitness effect of resistance between these sub-populations, thus creating niches for sensitivity and resistance. We then generalise this unified underlying model to multidrug resistance and show that models with this structure predict high levels of association between resistance to different drugs and high multidrug resistance frequencies. We test predictions from this model in six bacterial datasets and find them to be qualitatively consistent with observed trends. The higher than expected frequencies of multidrug resistance are often interpreted as evidence that these strains are out-competing strains with lower resistance multiplicity. Our work provides an alternative explanation that is compatible with long-term stability in resistance frequencies.
| S-EPMC6532944 | biostudies-literature
Project description:Alternating antibiotic therapy, in which pairs of drugs are cycled during treatment, has been suggested as a means to inhibit the evolution of de novo resistance while avoiding the toxicity associated with more traditional combination therapy. However, it remains unclear under which conditions and by what means such alternating treatments impede the evolution of resistance. Here, we tracked multistep evolution of resistance in replicate populations of Staphylococcus aureus during 22 d of continuously increasing single-, mixed-, and alternating-drug treatment. In all three tested drug pairs, the alternating treatment reduced the overall rate of resistance by slowing the acquisition of resistance to one of the two component drugs, sometimes as effectively as mixed treatment. This slower rate of evolution is reflected in the genome-wide mutational profiles; under alternating treatments, bacteria acquire mutations in different genes than under corresponding single-drug treatments. To test whether this observed constraint on adaptive paths reflects trade-offs in which resistance to one drug is accompanied by sensitivity to a second drug, we profiled many single-step mutants for cross-resistance. Indeed, the average cross-resistance of single-step mutants can help predict whether or not evolution was slower in alternating drugs. Together, these results show that despite the complex evolutionary landscape of multidrug resistance, alternating-drug therapy can slow evolution by constraining the mutational paths toward resistance.
| S-EPMC4210010 | biostudies-literature